Selinexor-Based Triplet Shows Tolerability With Dose Reductions in RRMM

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In the second article of a 2-part series, Sumit Madan, MD, talked about the manageable toxicity profile with the triplet therapy selinexor (Xpovio), bortezomib, and dexamethasone and how dose reductions led to tolerable outcomes in patients with relapsed/refractory multiple myeloma.

CASE SUMMARY

A 70-year-old White woman was diagnosed with stage I multiple myeloma and fluorescence in situ hybridization showed deletion 17p (del17p) in her disease. The patient had a prior medical history of stage 3 chronic kidney disease and moderate renal impairment. She declined autologous stem cell transplant, and received lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. She had a very good partial response (VGPR), so lenalidomide maintenance was continued. Two years later the patient relapsed after reporting mild fatigue but continued to work full-time​. Bone marrow plasma cells, light chains, and M protein were all rising, and her kidney function worsened to stage IV chronic kidney disease. The patient was then given daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone and had a VGPR. One year later, she experienced a second relapse of her disease with renal function continuing to decline. The patient was started on selinexor (Xpovio), bortezomib, and dexamethasone (SVd) based on her progressive renal impairment, del17p status, and prior therapies. She achieved a VGPR.

Targeted Oncology: How did this SVd perform for patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment in the BOSTON trial (NCT03110562)?

SUMMIT MADAN, MD: We always have several patients with myeloma with some degree of renal insufficiency. The overall response rates were significantly better in patients who had normal renal function [74.8%], but also in patients that had renal impairment [81.0%].1 If you look at the response rates, it clearly favored the complete regimen...for patients with poor kidney functions. So, certainly selinexor can be entertained as one of the options even in those patients with moderate to severe renal impairment.1

What was the safety profile of this triplet therapy?

We can characterize [some of the most common] adverse events [AEs] as any grade gastrointestinal-related AEs that can include nausea [50%], but there isn’t too much vomiting [21%].2 Then the cytopenias that we see are neutropenia [15%] and thrombocytopenia [60%], and then the third main AE [we see] in this patient population is fatigue [42%]. Those are the most common AEs that we see [with SVd], and it's important to note that we don't really see any AEs affecting the heart, the kidneys, the lungs, the liver, [or other major organs].

Sumit Madan, MD

Hematologist-Oncologist

Banner MD Anderson Cancer Center

Gilbert, AZ

Sumit Madan, MD

Hematologist-Oncologist

Banner MD Anderson Cancer Center

Gilbert, AZ

So, there were more cytopenias [in the SVd arm compared with bortezomib and dexamethasone], as well as a little bit more anemia [36% vs 23%]…but not too much fatigue as there was 13% grade 3 fatigue in the SVd arm compared with 1% [of patients in the bortezomib and dexamethasone group].... Treatment discontinuation due to AEs occurred in about 21% in the triplet arm vs 16% in the doublet arm, and dose modifications are given in almost all the patients that received the triplet.2 Peripheral neuropathy...is significantly higher in patients that were given [bortezomib and dexamethasone] compared with the triplet arm, but otherwise, overall toxicity was slightly higher in patients who received SVd.3

How do you handle treating patient’s nausea while they are on SVd?

I think you need to be a bit more aggressive, initially at least, so that the patients can be on the drug [routinely]. The guidelines [point out that you should] give ondansetron [Zofran] on the day of treatment, and for 2 days following, then at least a month of the olanzapine [Zyprexa].4 So, when I see these patients, I let them know that these are some of the symptoms that they can experience to set up expectations of what they could face. So that they're not caught unaware...and that you can be aggressive with their supportive care.

What is your approach to dose modification with this therapy in RRMM?

If you look at so many of our myeloma drugs, when they initially come out it's given [about] twice a week, and then the way it's really used is once a week, because of all the studies that show you can reduce the toxicity by using this drug [less], and we're not compromising on the efficacy.... We were able to decrease the AEs by using [selinexor] once a week. The rate of grade 3 or 4 thrombocytopenia came down significantly [from 58% to 39%] and rates of fatigue were cut in half [from 25% to 13%]....2

The recommendation for SVd is to start at 100 mg [once weekly] and then you keep decreasing the dose...going down from 100 mg to 80 mg, from 80 mg to 60 mg, and 60 mg to 40 mg.4 We should not be shy about decreasing [the dose for the] patients who are not tolerating it, because it is more important for the patients to be on this drug for as long as possible in order to get the maximum benefit. In the BOSTON study, most of the patients ended up on the 80 mg once weekly dose of selinexor.2

References

1. Delimpasi S, Mateos MV, Auner HW, et al. Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study. Am J Hematol. 2022;97(3):E83-E86. doi:10.1002/ajh.26434

2. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3

3. Mateos MV, Englehardt M, Lelu X, et al. Efficacy, survival and safety of selinexor, bortezomib and dexamethasone (SVd) in patients with lenalidomide-refractory multiple myeloma: subgroup data from the BOSTON trial. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P886. Accessed December 15, 2023. https://tinyurl.com/3efvuzn8

4. Xpovio. Prescribing information. Karyopharm Therapeutics; 2022. Accessed December 14, 2023. https://tinyurl.com/26fr7try

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